Materiały źródłowe

• #1 Epidermolysis Bullosa – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK599531/

  Epidermolysis bullosa (EB) defines a group of rare, inherited dermatoses that present with repeated blistering, erosions, and ulceration in response to seemingly disproportionate mechanical trauma. This occurs due to genetically-mediated skin fragility defects within the dermo-epidermal junction. […] Sixteen genes have been implicated in underpinning at least 30 observed epidermolysis bullosa subtypes. Each subtype features varying phenotypic severity and impact on morbidity and mortality. These subtypes have been organized into 4 major groups based on the ultrastructural plane within the dermo-epidermal junction that the defect impacts: […] The culmination of this dermo-epidermal junction malfunction is skin fragility. Erosions, blistering, and ulceration ensue in response to seemingly disproportionate mechanical trauma. The resultant wounds are frequently persistent, prone to chronic inflammation, susceptible to infection, and are associated with significant pruritis, pain, and diminished quality of life.

• #2 Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features – UpToDate

  https://www.uptodate.com/contents/epidemiology-pathogenesis-classification-and-clinical-features-of-epidermolysis-bullosa

  Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous inherited skin fragility disorder characterized by disruption of the skin’s structure at the dermoepidermal junction or in the basal layer of the epidermis, resulting in increased cutaneous vulnerability to mechanical stress. […] Depending on the specific genetic defect and its molecular sequelae, clinical hallmarks include blisters, wounds, and scars following minor trauma. […] The epidemiology, pathogenesis, and clinical features of EB are discussed in this topic.

• #3 Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives

  https://www.mdpi.com/1422-0067/25/17/9495

  Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma. The simplex form (EBS) is characterized by recurrent blister formation within the basal layer of the epidermis. It most often results from dominant mutations in the genes coding for keratin (K) 5 or 14 proteins (KRT5 and KRT14). A disruptive mutation in KRT5 or KRT14 will not only structurally impair the cytoskeleton, but it will also activate a cascade of biochemical mechanisms contributing to EBS. Skin lesions are painful and disfiguring and have a significant impact on life quality. […] Several key genes associated with EBS were identified as specific immunological mediators, keratins, and cell junction components. These data deepened the understanding of the EBS pathophysiology and revealed important functional biological processes, particularly inflammation. This review emphasizes the three EBS subtypes caused by dominant mutations on either KRT5 or KRT14 (localized, intermediate, and severe). It aims to summarize current knowledge about the EBS expression profiling pattern and predicted molecular mechanisms involved and to outline progress in therapy.

• #4 Epidermolysis bullosa – Wikipedia

  https://en.wikipedia.org/wiki/Epidermolysis_bullosa

  Epidermolysis bullosa (EB) is due to a mutation in at least one of 16 different genes. […] The underlying mechanism is a defect in attachment between or within the layers of the skin. Loss or diminished function of type VII collagen leads to weakness in the structural architecture of the dermal-epidermal junction (DEJ) and mucosal membranes. […] In people born with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin; even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. […] People with EB have an increased risk of malignancies (cancers) of the skin.

• #5 Inherited epidermolysis bullosa: update on the clinical and genetic aspects | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-inherited-epidermolysis-bullosa-update-on-articulo-S0365059620301719

  Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. […] Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. […] The genes associated with EB encode proteins with structural functions in the epidermis, in the basement membrane area or in the upper part of the dermis, being important for the integrity of the skin and for the adhesion between dermis and epidermis. […] Genetic changes that alter the dynamics and function of these proteins result in failure of the structures that provide mechanical stability to the epidermis (such as the keratin cytoskeleton and desmosomes) and to the basement membrane area (such as hemidesmosomes, focal adhesions, anchoring filaments, and anchoring fibrils).

• #6 Epidermolysis Bullosa: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1062939-overview

  Epidermolysis bullosa is a family of bullous disorders caused by an absence of basement membrane components due to underlying gene mutations. Epidermolysis bullosa is classified into four major categories: (1) epidermolysis bullosa simplex (intraepidermal skin separation), (2) junctional epidermolysis bullosa (skin separation in lamina lucida or central BMZ), (3) dystrophic epidermolysis bullosa (sublamina densa BMZ separation, as in the images below), and (4) Kindler syndrome (extremely rare, blistering at any level). […] Many stratified squamous epithelial tissues, such as the skin and oral mucosa, contain a complex basement membrane zone (BMZ). The BMZ is composed of many specialized components that combine to form anchoring complexes. At the superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell cytoskeleton insert on basal cell plasma membrane condensations termed hemidesmosomes.

• #7 Epidermolysis bullosa

  https://dermnetnz.org/topics/epidermolysis-bullosa

  Epidermolysis bullosa (EB) is a group of inherited diseases that are characterised by blistering lesions on the skin and mucous membranes. […] The EB conditions result from genetic defects of molecules in the skin concerned with adhesion. Loss of adhesion results in blister formation. […] There are four major types of EB based on different sites of blister formation within the skin structure: Epidermolysis bullosa simplex (EBS), Junctional epidermolysis bullosa (JEB), Dystrophic epidermolysis bullosa (DEB), and Kindler syndrome. […] The severity of EB can be assessed using the following scoring systems: The Birmingham EB score, The EBDASI: EB Activity and Scarring Index, The iSCOREB: an instrument for scoring clinical outcomes for research of EB, The QOLEB: Quality of life evaluation in EB. […] There is no cure for EB. However, significant research, including gene therapy and cell-based therapy, continue in the aim to improve quality of life.

• #8 New Hope for Treating the 4 Main Types of Epidermolysis Bullosa

  https://www.dermatologytimes.com/view/new-hope-for-treating-the-4-main-types-of-epidermolysis-bullosa

  Epidermolysis bullosa (EB) is an inherited, heterogenous group of rare genetic disorders characterized by blistering of the skin and mucosal fragility following minimal mechanical trauma and heat. […] The blistering lesions seen in EB can also occur spontaneously and are the result of the mutations in genes that encode basement membrane zone components of proteins that are responsible for maintaining the integrity of the basal membrane zone and adjacent keratinocytes. […] The division of these variants is based on the morphological level of separation within the dermal-epidermal junction zone and reflects the underlying molecular abnormality. In EBS, the blisters form within the epidermis; in JEB, they form within the lamina lucida of the basement membrane; in DEB, they form just below the basement membrane; and in KEB, there is a mixed skin cleavage pattern and blisters can occur at all levels of the skin.

• #9 Epidermolysis Bullosa – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK599531/

  Epidermolysis bullosa simplex arises when there is a defect in genes encoding proteins governing epidermal integrity. While epidermolysis bullosa simplex can be inherited in an autosomal dominant or autosomal recessive pattern, the former is more common. […] Junctional epidermolysis bullosa is characterized by blistering within the plane of the lamina lucida. An autosomal recessive inheritance pattern is observed. […] Dystrophic epidermolysis bullosa features fragility below the lamina densa due to mutant COL7A1 (collagen VII protein). […] Kindler epidermolysis bullosa is a consequence of an autosomal recessive defect in the FERMT1 gene, which produces faulty kindlin-1 proteins. This alters keratinocyte cytoskeleton maintenance and integrin activation. In Kindler epidermolysis bullosa, blistering may occur in any plane of the dermo-epidermal junction. […] The prognosis in epidermolysis bullosa is variable and dictated by the specific causative subtype and the complications arising from cutaneous and extracutaneous manifestations.

• #10 Epidermolysis Bullosa: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1062939-overview

  Type VII collagen is the primary component of anchoring fibrils. Type VII collagen contains a large N-terminal globular domain (NC-1), which interacts with laminin-332 in the lamina densa; a long collagenous domain; and a smaller C-terminal globular domain (NC-2), which is cleaved proteolytically during anchoring fibril formation. […] Most cases of epidermolysis bullosa simplex are associated with mutations of the genes coding for keratins 5 and 14. […] Junctional epidermolysis bullosa has a highly variable molecular etiology and represents a collection of different diseases. These diseases all cause blistering in the lamina lucida and variable hemidesmosomal abnormalities. […] Dystrophic epidermolysis bullosa thus far has been associated in all cases with mutations of the gene coding for type VII collagen (COL7A1). Anchoring fibrils are affected in patients with dystrophic epidermolysis bullosa, and the degree of involvement ranges from subtle changes to complete absence.

• #11

  https://www.jci.org/articles/view/38177

  Epidermolysis bullosa (EB) simplex is a rare genetic condition typified by superficial bullous lesions that result from frictional trauma to the skin. Most cases are due to dominantly acting mutations in either keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins tasked with forming a pancytoplasmic network of 10-nm filaments in basal keratinocytes of the epidermis and in other stratified epithelia. Defects in K5/K14 filament network architecture cause basal keratinocytes to become fragile and account for their trauma-induced rupture. […] Here we review how laboratory investigations centered on keratin biology have deepened our understanding of the etiology and pathophysiology of EB simplex and revealed novel avenues for its therapy. […] In EB simplex, trauma-induced loss of tissue integrity consistently occurs within the basal layer of epidermal keratinocytes. The inherited defect renders basal keratinocytes fragile, causing them to rupture when the epidermis (and, in some cases, other stratified epithelia) is subjected to mechanical stress. […] Despite the considerable progress made since then, developing successful therapies for EB simplex has proven to be challenging. There is reason to be cautiously optimistic, however, since recent discoveries made in studies of its pathophysiology have led to new ideas for therapy.

• #12 Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives

  https://www.mdpi.com/1422-0067/25/17/9495

  In EBS, causal mutations can impact the structure of these proteins, causing keratin aggregates in keratinocytes, triggering endoplasmic reticulum stress and leading to the release of pro-inflammatory molecules. Intraepidermal ruptures occur and lead to loss of tissue integrity and severe blistering of the epidermis upon mechanical trauma or traction. […] The common agreement that surfaced is the potential implication of inflammation in EBS pathogenesis as well as the possibilities of efficient treatment development. […] A variety of immune cell types migrate, proliferate, and produce cytokines, interleukins (ILs), and interferons (IFNs) in an orchestrated manner at the inflammation site. Aside from the keratin defaults triggering EBS, it becomes clear that this disorder is associated with inflammation as reported by transcriptomic analysis. Various signaling inflammatory pathways were shown to be involved in the EBS pathomechanisms.

• #13

  https://www.jci.org/articles/view/38177

  Studies carried out in relevant mouse models confirmed that frictional trauma, often in a repeated fashion, is required to expose the fragility of basal keratinocytes and elicit bullous skin lesions. Subsequent biophysical studies conducted on keratin IFs, both when reconstituted in vitro and in cultured cells ex vivo, strongly suggested that mutant keratin-expressing basal keratinocytes are mechanically softer due to defects in the architecture of the IF network. […] The presence of cytoplasmic aggregates containing mispolymerized mutant keratin proteins is the defining characteristic of EBS-DM and may worsen the impact of dominant-negative mutations. […] Elucidating the genetic basis of EB simplex has had a significant impact on skin biology and dermatology. It established that inherited defects in a structural protein, even when small (e.g., a missense mutation), can ultimately compromise the function of the large array of interconnected intracellular and extracellular protein polymers tasked with maintaining the integrity of skin tissue. […] Understanding more about the molecular mechanisms underlying their regulation might offer new insights into how one might control the expression of these genes for therapeutic purposes.

• #14 Inherited epidermolysis bullosa: update on the clinical and genetic aspects | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-inherited-epidermolysis-bullosa-update-on-articulo-S0365059620301719

  The characteristic phenotype of the different forms of EB is correlated to the gene that is altered. […] Different genes also lead to very similar EB phenotypes, which adds complexity to the understanding of the associated pathogenic mechanisms. […] The type of genetic alteration and its consequence for protein expression are directly linked to the phenotypic severity of recessive dystrophic EB (RDEB). […] Pathogenic variants in the genes that encode the components of the dermoepidermal junction result in the absence or disturbance of their functions and the consequent decrease in adhesion of the skin layers, which leads to the characteristic JEB phenotypes. […] Pathogenic variants in the LAMA3, LAMB3, or LAMC2 genes lead to the absence or reduction of laminin 332, which results in the loss of its function as a bridge between hemidesmosomes and anchoring fibrils.

• #15

  https://link.springer.com/article/10.1007/s13555-024-01227-8

  Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermaldermal adhesion and stability. […] The most common type, EB simplex (EBS), involving skin cleavage within the basal epidermal layer, is also the most heterogeneous genetically and clinically. […] The second most common is dystrophic EB (DEB), characterized by a split in the upper dermis due to genetic defects of type VII collagen (C7). Junctional EB (JEB) is very rare; it is caused by mutations in genes encoding transmembrane proteins of the hemidesmosomes, focal adhesions, or the basement membrane laminin 332. […] Mucocutaneous fragility causes blisters and wounds, tissue damage, breakage of the cutaneous barrier, chronic bacterial colonization of the skin, inflammation, and, depending on the level of cleavage, scarring.

• #16 Epidermolysis Bullosa – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/epidermolysis-bullosa

  Epidermolysis bullosa is a group of inherited disorders that involve various genetic mutations. […] Genetically mediated defects in epithelial adhesion proteins result in skin and mucous membrane fragility, which predisposes the epithelium to easy bullae formation after minor trauma or sometimes spontaneously. […] In dystrophic epidermolysis bullosa, mutations occur in the type VII collagen gene.

• #17 Dystrophic Epidermolysis Bullosa: Pathogenesis and Clinical Features | Plastic Surgery Key

  https://plasticsurgerykey.com/dystrophic-epidermolysis-bullosa-pathogenesis-and-clinical-features/

  In most patients with most severe recessive DEB, both COL7A1 mutations cause premature termination codons (PTC), which lead to nonsense mediated mRNA decay, or residual expression of truncated collagen VII polypeptides that are degraded within the cell. […] In dominant DEB, heterozygous glycine substitution mutations interfere in a dominant-negative manner with collagen VII synthesis and impair its secretion or the fibrillogenesis of the AF. […] Two different mouse models with complete or partial deficiency of collagen VII recapitulate the clinical and morphologic characteristics of recessive DEB in people and have been useful for understanding the molecular pathology of the disease.

• #18 Recessive Dystrophic Epidermolysis Bullosa A Review of Disease Pathogenesis and Update on Future Therapies | JCAD – The Journal of Clinical and Aesthetic Dermatology

  https://jcadonline.com/recessive-dystrophic-epidermolysis-bullosa-a-review-of-disease-pathogenesis-and-update-on-future-therapies/

  Any inherited predisposition to altered formation of C7 or its anchoring fibrils leads to dystrophic EB. More than 700 different mutations of COL7A1 have been reported. […] In RDEB, missense or nonsense mutations occur on both alleles of COL7A1. Genetic compound heterozygosity is common in these patients as they inherit one type of COL7A1 mutation from one parent and a different type from the other. […] Interestingly, a recent report of RDEB occurring in monozygotic twins with identical COL7A1 mutations yet very different disease severity highlights that other variables contribute to phenotypic diversity as well. […] Clinically, RDEB-GS patients present with involvement over much of the integument, including the mucous membranes. […] Management of patients with RDEB is presently limited to wound care and attempts to minimize trauma.

• #19 Epidermolysis Bullosa: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1062939-overview

  Duplication of the basement membrane is characteristically seen by electron microscopy, along with a variable level of skin separation, either sublamina densa (most common) intralamina lucida, or intraepidermal. Kindlin-1, a protein similar to talin, shows deficient expression in this disease. Mutations of the KIND1 gene coding for kindlin-1 have been associated with this disease.

• #20 Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01467-9

  Hereditary epidermolysis bullosa (EB) comprises a heterogeneous group of rare genodermatoses, which are caused by mutations in genes involved in the maintenance of the structural and functional integrity of dermo-epidermal adhesion in various stratified epithelia. […] Chronic tissue damage with induction and dysregulation of inflammatory pathways is a common pathogenic mechanism in EB as a mutation-based barrier disorder, although inter- and intra-individual variability of immune responses remains to be determined. […] While in localized EB variants inflammatory aberrations mainly affect the micromilieu of lesional skin (leading to tissue remodeling), a systemic impact was shown in severe subtypes such as RDEB, in which extensive cutaneous involvement is associated with a systemic inflammatory response and chronification of inflammatory cascades that contribute to the systemic morbidity of EB.

• #21 Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives

  https://www.mdpi.com/1422-0067/25/17/9495

  Increased expression of IL-1β was also shown in keratinocytes derived from one patient with EBS-sev. Upregulation of IL-6, IL-8, and IL-10 was also observed in the epidermis of patients with either KRT5 or KRT14 mutations. This is consistent with local inflammation that can accompany EBS lesions. […] This highlights the role of inflammation in exacerbating the EBS phenotype, particularly in EBS-sev. […] Higher levels of Th17 immune response markers such as IL-17, IL-21, and IL-22 were observed in the blister roof of patients with EBS-sev compared with controls by analysis of cytokine mRNA expression. […] Altogether, these results strongly suggest the involvement of the Th17 immune response in the EBS pathogenesis. […] The expression profile of EBS represents a lengthy list of dysregulated genes. […] The knowledge generated regarding the potential of inflammation components as therapeutic targets and the explosion of omics data combined with new genome editing approaches provided powerful insights for EBS.

• #22 Epidermolysis Bullosa Acquisita: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1063083-overview

  Epidermolysis bullosa acquisita (EBA) is caused by antibodies targeting type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. […] Epidermolysis bullosa acquisita (EBA) is characterized by the presence of IgG autoantibodies targeting the noncollagenous (NC1) domain of type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. A subset of patients have variations in which either IgG autoantibodies bind the central triple-helical collagenous (NC2) domain of type VII collagen, or immunoglobulin A (IgA), rather than IgG, targets type VII collagen. […] The targeting of the NC2 domain by autoantibodies may destabilize anchoring fibrils by interfering with antiparallel dimer formation, leading to dermoepidermal disadherence.

• #23 Epidermolysis Bullosa Acquisita—Current and Emerging Treatments

  https://www.mdpi.com/2077-0383/12/3/1139

  Epidermolysis bullosa acquisita (EBA) is a rare chronic autoimmune subepidermal blistering disease of the skin and mucous membranes, usually beginning in adulthood. EBA is induced by autoantibodies to type VII collagen, a major component of anchoring fibrils in the dermal–epidermal junction (DEJ). The binding of autoantibodies to type-VII collagen subsequently leads to the detachment of the epidermis and the formation of mucocutaneous blisters. […] Pathophysiologic events could be divided into three phases: loss of tolerance to COL7 (induction or afferent phase), autoantibody production, and autoantibody-induced tissue damage (effector of efferent phase). […] EBA susceptibility is associated with genes in and outside the major histocompatibility complex (MHC) locus. Specifically, Gammon et al. documented an association with MHC locus HLA-DR2.

• #24 Epidermolysis Bullosa Acquisita: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1063083-overview

  These antibodies compromise the strength of the basement membrane zone, leading to skin fragility and trauma-induced blister formation. […] Various murine models have contributed to the understanding of the pathogenic role of antitype VII collagen antibodies and pathophysiology of epidermolysis bullosa acquisita. […] The failure of rabbit antimouse type VII collagen antibodies to induce blisters in C5-deficient mice supports a role for complement activation in the disease pathogenesis. […] Immunization of type VII collagen in athymic nude SJL mice did not induce an autoimmune response, whereas the repletion of T cells from type VII collagenimmunized wild-type mice to the thymic mice showed autoantibody production and resulted in a blistering disease phenotype, supporting the role of T cells in the induction of epidermolysis bullosa acquisita. […] The fact that epidermolysis bullosa acquisita is responsive to rituximab antibody to CD20 supports the role of B cells.

• #25 Pathogenesis of Epidermolysis Bullosa Acquisita | Plastic Surgery Key

  https://plasticsurgerykey.com/pathogenesis-of-epidermolysis-bullosa-acquisita-2/

  Without exception, autoantibody-induced tissue injury in all available experimental models of EBA depends on the Fc fragment of IgG. […] Release of reactive oxygen species (ROS) and proteolytic enzymes is a key event in neutrophil activation. […] Neutrophils are the main effector cells for blister formation and tissue injury. […] Blister formation in experimental models of EBA clearly depends on the autoantibodies isotype, complement activation, neutrophils, production of ROS, and release of proteolytic enzymes.

• #26

  https://omim.org/entry/226600

  A defect in collagenase (MMP1; 120353) was implicated early on in the pathogenesis of dystrophic epidermolysis bullosa. Type VII collagen is susceptible to degradation by collagenase (Seltzer et al., 1989). […] Bauer (1977) found that procollagenase purified from fibroblasts of 2 patients with DEB was more thermolabile, showed decreased calcium affinity, and had decreased activity in vitro compared to control values. […] Bauer and Eisen (1978) observed enhanced collagenase production by cultured skin fibroblasts in 8 of 10 patients with autosomal recessive dystrophic epidermolysis bullosa. Increased levels of immunoreactive collagenase were found in unaffected and affected areas of the skin. […] Titeux et al. (2008) found a significant association between a polymorphism (rs1799750) in the MMP1 gene (120353.0001) and disease severity in 3 affected members of an RDEB family who were discordant for the SNP. The observations were confirmed in a cohort of 31 unrelated French RDEB patients: the functional SNP resulting in increased collagenase activity was associated with more severe phenotype (p = 6.27 x 10(-5)). Titeux et al. (2008) concluded that increased MMP1 leads to increased collagen degradation and worsening disease severity, suggesting that MMP1 is a modifier gene in RDEB.

• #27

  https://link.springer.com/article/10.1007/s13555-024-01227-8

  Thus, wounds are the central element in the pathogenesis of long-term disease manifestations and complications including failure to thrive, anemia, scarring, strictures, and skin cancer in some of the EB types (such as dystrophic, junctional, and Kindler EB). […] Extensive effort has been put into research into novel therapeutic approaches for EB during the past 30 years. The repair or replacement of EB-associated genes or proteins by gene or protein therapy has proven to be more challenging than expected. […] Repurposing drugs for EB treatment came into the focus of researchers around 15 years ago. There are various mechanisms by which such drugs interfere with EB pathogenesis: read-through of nonsense mutations, suppression of inflammation, suppression of fibrosis, etc. […] The pathogenesis chain in severe EB, in particular DEB. Skin fragility and wounds are the initial manifestations of EB and lead to cutaneous and systemic complications. Thus, corrective therapies aiming at the addition of type VII collagen into the skin are a meaningful approach.

• #28 Growth Impaired Children with Epidermolysis Bullosa have Increased Serum Markers of Inflammation and Reduced Circulating IGF-1/IGFBP-3 | Pediatric Research

  https://www.nature.com/articles/pr2011519

  Epidermolysis bullosa (EB) is a group of devastating diseases in which patients have skin inflammation with epithelial fragility and recurrent blistering. […] Pro-inflammatory cytokines impair growth in children with inflammatory bowel disease by inhibiting signal transduction from growth hormone (GH) to insulin-like growth factor-1 (IGF-1). We hypothesised that a similar mechanism occurred in EB. […] Children with severe generalised RDEB have poor growth and low circulating IGF-1 and IGFBP-3. This is likely to be due, in part, to inflammation. Correcting growth retardation will require non-steroidal therapies targeted at reducing inflammation.

• #29

  https://journals.lww.com/idoj/fulltext/2019/10030/newer_treatment_modalities_in_epidermolysis.3.aspx

  The genetic mechanisms of the reversion have been characterized, and a successful clinical application of small split thickness grafts derived from revertant skin was reported in an individual with JEB. […] Current clinical trials are studying the effects of different kinds of MSC in adults with EB. […] The rationale here is that antisense oligonucleotide treatment of cells can lead to skipping of the mutated exons at the RNA level, and thus restore the synthesis of a nearly normal protein that lacks a small fragment encoded by the deleted exon. […] In the context of EB, the collagen VII gene and its disease, DEB, have been of particular interest. […] Since progressive soft tissue fibrosis is a major systemic feature in DEB and a prerequisite for development of secondary squamous cell carcinoma, small molecule drugs which reduce inflammation and fibrosis may be useful to postpone mitten deformities, joint contractures, and internal strictures. […] In DEB, inflammation and TGF- signaling are major drivers of fibrosis and, therefore, losartan seems promising as a symptom-relief therapy. […] It will be intriguing to follow the progress of this therapeutic approach into clinical trials.

• #30

  https://link.springer.com/article/10.1007/s13555-024-01227-8

  The repetitive tissue damage and progressive scarring in RDEB are mainly driven by Transforming growth factor- (TGF-), suggesting that therapies that reduce TGF- signaling could slow disease progression and alleviate morbidity. […] Losartan, an anti-hypertensive medication, can attenuate TGF- signaling. Its efficacy was assessed in a col7a1 hypomorphic mouse model, where it delayed paw scarring and digit fusion, indicating a potential for human RDEB therapy. […] Another approach to reduce TGF- activity in the skin involves increasing the expression of decorin, a stromal proteoglycan that inhibits TGF- by binding to its core protein, preventing its interaction with receptors.

• #31

  https://omim.org/entry/226600

  A number sign (#) is used with this entry because autosomal recessive dystrophic epidermolysis bullosa (RDEB) and the RDEB localisata variant are caused by homozygous or compound heterozygous mutation in the gene encoding type VII collagen (COL7A1; 120120) on chromosome 3p21. […] Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disorder beginning at birth and characterized by recurrent blistering at the level of the sublamina densa beneath the cutaneous basement membrane. This results in mutilating scarring and contractures of the hands, feet, and joints. Patients also developed strictures of the gastrointestinal tract from mucosal involvement, which can lead to poor nutrition. Affected individuals have an increased risk of developing aggressive squamous cell carcinoma (Christiano et al., 1996; Varki et al., 2007).

• #32 Dystrophic epidermolysis bullosa: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/dystrophic-epidermolysis-bullosa/

  Dystrophic epidermolysis bullosa is one of the major forms of a group of conditions called epidermolysis bullosa. […] Mutations in the COL7A1 gene cause all forms of dystrophic epidermolysis bullosa. This gene provides instructions for making a protein that forms the pieces (subunits) of a larger protein called type VII collagen. […] COL7A1 gene mutations alter the structure or disrupt the production of the type VII collagen subunit protein. These changes affect the production of type VII collagen. […] When type VII collagen is abnormal or missing, the formation of anchoring fibrils is impaired. A shortage of these fibrils disrupts the connection of the epidermis to the dermis, and friction or other minor trauma can cause the two skin layers to separate. This separation leads to the formation of blisters, which can cause extensive scarring as they heal. […] Researchers are working to determine how abnormalities of type VII collagen also underlie the increased risk of skin cancer seen in RDEB-sev gen.

• #33 New Hope for Treating the 4 Main Types of Epidermolysis Bullosa

  https://www.dermatologytimes.com/view/new-hope-for-treating-the-4-main-types-of-epidermolysis-bullosa

  Paller said if all goes well, the next few years may be witness to several effective treatments, which is a very promising outlook for a disease that largely could only be treated symptomatically. […] We are finally being able to start looking at pathogenesis-directed approaches for these diseases as we learn more about not just the underlying genetic causes but also some of the pathways involved in the phenotypes that we see, she said.

• #34 FDA Approves Prademagene Zamikeracel for Recessive Dystrophic Epidermolysis Bullosa

  https://www.ajmc.com/view/fda-approves-prademagene-zamikeracel-for-recessive-dystrophic-epidermolysis-bullosa

  RDEB is 1 of 2 main subtypes of dystrophic epidermolysis bullosa, a severe genetic skin disorder. […] The main treatment strategies being explored are gene therapy, fibroblast cell therapy, bone marrow stem cell therapy, and protein therapy, with gene therapy appearing the most promising for RDEB. […] „[Prademagene zamikeracel] was well-tolerated and efficacious in clinical studies, providing clinically meaningful improvements in wound healing, pain reduction, and other associated symptoms in large chronic RDEB wounds after a single application, Jean Tang, MD, PhD, professor of dermatology and lead principal investigator of the VIITAL study, said in a statement. In the completed phase 1/2a study of [prademagene zamikeracel], we have observed wound healing and pain reduction that have lasted for years after a single application.”

• #35 Recessive Dystrophic Epidermolysis Bullosa A Review of Disease Pathogenesis and Update on Future Therapies | JCAD – The Journal of Clinical and Aesthetic Dermatology

  https://jcadonline.com/recessive-dystrophic-epidermolysis-bullosa-a-review-of-disease-pathogenesis-and-update-on-future-therapies/

  Fortunately, significant progress has been made in the last decade in devising innovative, molecularly based, curative therapies for EB patients. […] Gene therapy is perhaps the most promising avenue for treatment of RDEB. […] One drawback to the gene therapy approach is that in cases of ex vivo gene transfer, there are questions regarding the possibility of developing an immune response to newly produced C7, particularly in patients who are completely deficient of the protein, such as those with RDEB-GS. […] A therapeutic option perhaps closer to regular clinical application than gene therapy is injection of fibroblasts derived from unaffected donors. […] Bone marrow-derived mesenchymal stem cells have also shown potential for treatment of RDEB. […] Successful preliminary studies where investigators injected purified human C7 protein into RDEB mice have led to optimism for use of this strategy in RDEB patients. […] RDEB is among the most severe genodermatoses known, but treatment is currently limited to wound care, avoidance of trauma, active screening for SCC, and general supportive care with a multidisciplinary approach.

• #36

  https://link.springer.com/article/10.1007/s13555-024-01227-8

  Gene editing techniques like clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) offer the potential for treating EB by correcting mutations and improving gene correction efficacy in patient-derived cells, enabling the development of functional collagen-synthesizing skin grafts. […] Challenges include the need for a large quantity of cultured cells, which is addressed through solutions like iPSCs. […] The read-through approach utilizes small-molecular-weight compounds to enable the translational machinery to suppress nonsense mutations by inserting an amino acid in place of a premature stop codon, thereby facilitating the synthesis of full-length proteins. […] The original prototype of such read-through molecules, PTC124 (ataluren), has shown the ability to bypass pathogenic premature termination codons (PTCs), but it fails to efficiently override naturally occurring endogenous stop codons of translation.

• #37 Krystal Biotech Announces First Quarter 2025 Financial and Operating Results | Krystal Biotech, Inc.

  https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-first-quarter-2025-financial-and

  VYJUVEK is a non-invasive, topical, redosable gene therapy designed to deliver two copies of the COL7A1 gene when applied directly to DEB wounds. VYJUVEK was designed to treat DEB at the molecular level by providing the patient’s skin cells the template to make normal COL7 protein, thereby addressing the fundamental disease-causing mechanism. […] VYJUVEK is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy indicated for the treatment of wounds in patients six months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

• #38 Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01467-9

  Against this background, the induction of inflammatory traits defines new therapeutic targets including skin barrier restoration, infection control/surveillance, immune response/modulation, anti-neoplastic interference and interference with epigenetic drivers of the disease. […] Based on the increasing knowledge on EB subtype-specific pathomechanisms, first candidates have reached clinical development, and first marketing approvals are awaited in the near future. […] This renders them more specific and potentially more efficient and safe. […] Diacerein, a small molecule derived from the rhubarb root, can interfere with the IL-1 mediated inflammatory pathway at several levels. […] In summary, recent clinical trials are based on increasing understanding of pathomechanisms, resulting in more targeted approaches with clearly defined mechanisms of action of the investigational product.

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